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Theranostics 2024The availability of non-invasive drug delivery systems capable of efficiently transporting bioactive molecules across the blood-brain barrier to specific cells at the...
The availability of non-invasive drug delivery systems capable of efficiently transporting bioactive molecules across the blood-brain barrier to specific cells at the injury site in the brain is currently limited. Delivering drugs to neurons presents an even more formidable challenge due to their lower numbers and less phagocytic nature compared to other brain cells. Additionally, the diverse types of neurons, each performing specific functions, necessitate precise targeting of those implicated in the disease. Moreover, the complex synthetic design of drug delivery systems often hinders their clinical translation. The production of nanomaterials at an industrial scale with high reproducibility and purity is particularly challenging. However, overcoming this challenge is possible by designing nanomaterials through a straightforward, facile, and easily reproducible synthetic process. In this study, we have developed a third-generation 2-deoxy-glucose functionalized mixed layer dendrimer () utilizing biocompatible and cost-effective materials a highly facile convergent approach, employing copper-catalyzed click chemistry. We further evaluated the systemic neuronal targeting and biodistribution of , and brain delivery of a neuroprotective agent pioglitazone () in a pediatric traumatic brain injury (TBI) model. The exhibits favorable characteristics including high water solubility, biocompatibility, biological stability, nanoscale size, and a substantial number of end groups suitable for drug conjugation. Upon systemic administration in a pediatric mouse model of traumatic brain injury (TBI), the localizes in neurons at the injured brain site, clears rapidly from off-target locations, effectively delivers , ameliorates neuroinflammation, and improves behavioral outcomes. The promising results coupled with a convenient synthetic approach for the construction of makes it a potential nanoplatform for addressing brain diseases.
Topics: Animals; Dendrimers; Neurons; Drug Delivery Systems; Deoxyglucose; Neuroprotective Agents; Mice; Pioglitazone; Blood-Brain Barrier; Brain Injuries, Traumatic; Brain; Brain Diseases; Humans; Disease Models, Animal; Tissue Distribution; Male
PubMed: 38855177
DOI: 10.7150/thno.95476 -
BMC Cancer Jun 2024The axillary lymph-node metastatic burden is closely associated with treatment decisions and prognosis in breast cancer patients. This study aimed to explore the value...
BACKGROUND
The axillary lymph-node metastatic burden is closely associated with treatment decisions and prognosis in breast cancer patients. This study aimed to explore the value of F-fluorodeoxyglucose (F-FDG) positron emission tomography (PET)/computed tomography (CT)-based radiomics in combination with ultrasound and clinical pathological features for predicting axillary lymph-node metastatic burden in breast cancer.
METHODS
A retrospective analysis was conducted and involved 124 patients with pathologically confirmed early-stage breast cancer who had undergone F-FDG PET/CT examination. The ultrasound, PET/CT, and clinical pathological features of all patients were analysed, and radiomic features from PET images were extracted to establish a multi-parameter predictive model.
RESULTS
The ultrasound lymph-node positivity rate and PET lymph-node positivity rate in the high nodal burden group were significantly higher than those in the low nodal burden group (χ = 19.867, p < 0.001; χ = 33.025, p < 0.001). There was a statistically significant difference in the PET-based radiomics score (RS) for predicting axillary lymph-node burden between the high and low lymph-node burden groups. (-1.04 ± 0.41 vs. -1.47 ± 0.41, t = -4.775, p < 0.001). The ultrasound lymph-node positivity (US_LNM) (odds ratio [OR] = 3.264, 95% confidence interval [CI] = 1.022-10.423), PET lymph-node positivity (PET_LNM) (OR = 14.242, 95% CI = 2.960-68.524), and RS (OR = 5.244, 95% CI = 3.16-20.896) are all independent factors associated with high lymph-node burden (p < 0.05). The area under the curve (AUC) of the multi-parameter (MultiP) model was 0.895, which was superior to those of US_LNM, PET_LNM, and RS models (AUC = 0.703, 0.814, 0.773, respectively), with statistically significant differences (Z = 2.888, 3.208, 3.804, respectively; p = 0.004, 0.002, < 0.001, respectively). Decision curve analysis indicated that the MultiP model provided a higher net benefit for all patients.
CONCLUSION
A MultiP model based on PET-based radiomics was able to effectively predict axillary lymph-node metastatic burden in breast cancer.
TRIAL REGISTRATION
This study was registered with ClinicalTrials.gov (registration number: NCT05826197) on May 7, 2023.
Topics: Humans; Female; Breast Neoplasms; Positron Emission Tomography Computed Tomography; Fluorodeoxyglucose F18; Middle Aged; Lymphatic Metastasis; Retrospective Studies; Axilla; Adult; Aged; Lymph Nodes; Radiopharmaceuticals; Prognosis; Neoplasm Staging; Radiomics
PubMed: 38849770
DOI: 10.1186/s12885-024-12476-3 -
BMC Cancer Jun 2024[F]Fluorodeoxyglucose ([F]FDG) positron emission tomography (PET) is recommended during diagnostic work-up for ovarian cancer; however, [F]FDG PET has several inherent...
BACKGROUND
[F]Fluorodeoxyglucose ([F]FDG) positron emission tomography (PET) is recommended during diagnostic work-up for ovarian cancer; however, [F]FDG PET has several inherent limitations. The novel oncologic PET-tracer fibroblast activation protein inhibitor (FAPI) has demonstrated promising results in multiple cancer types, including ovarian cancer, and could overcome the limitations of [F]FDG PET; however, high-quality clinical studies are lacking. The primary objective of the present study is to compare the diagnostic accuracy of [Ga]Ga-FAPI-46 PET/CT and [F]FDG PET/CT in ovarian cancer patients and to investigate how this potential difference impacts staging and patient management.
METHODS AND DESIGN
Fifty consecutive ovarian cancer patients will be recruited from Aalborg University Hospital, Denmark. This study will be a single-center, prospective, exploratory clinical trial that adheres to the standards for reporting diagnostic accuracy studies (STARD). This study will be conducted under continuous Good Clinical Practice monitoring. The eligibility criteria for patients are as follows: (1) biopsy verified newly diagnosed ovarian cancer or a high risk of ovarian cancer and referred for primary staging with [F]FDG PET/CT; and (2) resectable disease, i.e., candidate for primary debulking surgery or neoadjuvant chemotherapy followed by interval debulking surgery. All recruited study subjects will undergo [Ga]Ga-FAPI-46 PET/CT at primary staging, before primary debulking surgery or neoadjuvant chemotherapy (Group A + B), in addition to conventional imaging (including [F]FDG PET/CT). Study subjects in Group B will undergo an additional [Ga]Ga-FAPI-46 PET/CT following neoadjuvant chemotherapy prior to interval debulking surgery. The results of the study-related [Ga]Ga-FAPI-46 PET/CTs will be blinded, and treatment allocation will be based on common clinical practice in accordance with current guidelines. The histopathology of surgical specimens will serve as a reference standard. A recruitment period of 2 years is estimated; the trial is currently recruiting.
DISCUSSION
To our knowledge, this trial represents the largest, most extensive, and most meticulous prospective FAPI PET study conducted in patients with ovarian cancer thus far. This study aims to obtain a reliable estimation of the diagnostic accuracy of [Ga]Ga-FAPI-46 PET/CT, shed light on the clinical importance of [Ga]Ga-FAPI-46 PET/CT, and examine the potential applicability of [Ga]Ga-FAPI-46 PET/CT for evaluating chemotherapy response.
TRIAL REGISTRATION
clinicaltrials.gov: NCT05903807, 2nd June 2023; and euclinicaltrials.eu EU CT Number: 2023-505938-98-00, authorized 11th September 2023.
Topics: Humans; Female; Positron Emission Tomography Computed Tomography; Ovarian Neoplasms; Prospective Studies; Neoplasm Staging; Fluorodeoxyglucose F18; Gallium Radioisotopes; Radiopharmaceuticals; Middle Aged; Adult; Aged; Quinolines
PubMed: 38849741
DOI: 10.1186/s12885-024-12461-w -
Biomedicine & Pharmacotherapy =... Jul 2024Metastasis is the leading cause of cancer-related deaths, making the development of novel, more effective therapies imperative to alleviate patient suffering. Metabolic...
Metastasis is the leading cause of cancer-related deaths, making the development of novel, more effective therapies imperative to alleviate patient suffering. Metabolic switching is a hallmark of cancer cells that facilitates metastasis. Cancer cells obtain most of their energy and intermediate metabolites, which are required to proliferate and metastasize, through aerobic glycolysis. Previous work from our laboratory has shown that Caveolin-1 (CAV1) expression in cancer cells promotes glycolysis and metastasis. Here, we sought to determine if limiting glycolysis reduced CAV1-enhanced metastasis and to identify the mechanism(s) involved. We evaluated the effects of the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) in metastatic melanoma and breast cancer cell lines expressing or not CAV1. Non-cytotoxic concentrations of 2-DG (1 mM) inhibited the migration of B16-F10 melanoma and MDA-MB-231 breast cancer cells. CAV1-mediated activation of Src/Akt signaling was required for CAV1-enhanced migration and was blocked in the presence of 2-DG. Moreover, inhibition of Akt reduced CAV1-enhanced lung metastasis of B16-F10 cells. Collectively, these findings highlight the importance of CAV1-induced metabolic reprogramming for metastasis and point towards possible therapeutic approaches to prevent metastatic disease by inhibiting glycolysis and Src/Akt signaling.
Topics: Caveolin 1; Glycolysis; Proto-Oncogene Proteins c-akt; Animals; Signal Transduction; src-Family Kinases; Humans; Cell Line, Tumor; Mice; Cell Movement; Deoxyglucose; Female; Neoplasm Metastasis; Melanoma, Experimental; Breast Neoplasms; Lung Neoplasms; Mice, Inbred C57BL
PubMed: 38834004
DOI: 10.1016/j.biopha.2024.116841 -
Cancer Imaging : the Official... Jun 2024This study investigates the value of fluorine 18 ([F])-labeled fibroblast activation protein inhibitor (FAPI) for lymph node (LN) metastases in patients with stage...
BACKGROUND
This study investigates the value of fluorine 18 ([F])-labeled fibroblast activation protein inhibitor (FAPI) for lymph node (LN) metastases in patients with stage I-IIIA non-small cell lung cancer (NSCLC).
METHODS
From November 2021 to October 2022, 53 patients with stage I-IIIA NSCLC who underwent radical resection were prospectively included. [F]-fluorodeoxyglucose (FDG) and [F]FAPI examinations were performed within one week. LN staging was validated using surgical and pathological findings. [F]FDG and [F]FAPI uptake was compared using the Wilcoxon signed-ranks test. Furthermore, the diagnostic value of nodal groups was investigated.
RESULTS
In 53 patients (median age, 64 years, range: 31-76 years), the specificity of [F]FAPI for detecting LN metastasis was significantly higher than that of [F]FDG (P < 0.001). High LN risk category, greater LN short-axis dimension(≥ 1.0 cm), absence of LN calcification or high-attenuation, and higher LN FDG SUV (≥ 10.1) were risk factors for LN metastasis(P < 0.05). The concurrence of these four risk factors accurately predicted LN metastases (Positive Predictive Value [PPV] 100%), whereas the presence of one to three risk factors was unable to accurately discriminate the nature of LNs (PPV 21.7%). Adding [F]FAPI in this circumstance improved the diagnostic value. LNs with an [F]FAPI SUV<6.2 were diagnosed as benign (Negative Predictive Value 93.8%), and LNs with an [F]FAPI SUV≥6.2 without calcification or high-attenuation were diagnosed as LN metastasis (PPV 87.5%). Ultimately, the integration of [F]FDG and [F]FAPI PET/CT resulted in the highest accuracy for N stage (83.0%) and clinical decision revisions for 29 patients.
CONCLUSION
In patients with stage I-IIIA NSCLC, [F]FAPI contributed additional valuable information to reduce LN diagnostic uncertainties after [F]FDG PET/CT. Integrating [F]FDG and [F]FAPI PET/CT resulted in more precise clinical decisions.
TRIAL REGISTRATION
The Chinese Clinical Trial Registry: ChiCTR2100044944 (Registered: 1 April 2021, https://www.chictr.org.cn/showprojEN.html?proj=123995 ).
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Middle Aged; Male; Female; Lung Neoplasms; Prospective Studies; Fluorodeoxyglucose F18; Aged; Positron Emission Tomography Computed Tomography; Adult; Lymphatic Metastasis; Radiopharmaceuticals; Neoplasm Staging; Lymph Nodes
PubMed: 38831354
DOI: 10.1186/s40644-024-00701-y -
Biomolecules & Biomedicine Jun 2024Cerebral aneurysms (CA) are critical conditions often associated with oxidative stress in vascular endothelial cells (VECs). The enzyme lactate dehydrogenase A (LDHA)...
Cerebral aneurysms (CA) are critical conditions often associated with oxidative stress in vascular endothelial cells (VECs). The enzyme lactate dehydrogenase A (LDHA) plays a crucial role in glycolysis and lactate metabolism, processes implicated in the pathogenesis of aneurysms. Understanding these molecular mechanisms can inform the development of novel therapeutic targets. This study investigated the role of lactate metabolism and lactate-related genes, particularly LDHA and vascular endothelial growth factor A (VEGFA) genes, in VECs during oxidative stress. Using the GSE26969 dataset, we identified differential expression of lactate-related genes and performed functional enrichment analysis, revealing significant associations with glycolysis and lactate metabolic pathways. To induce oxidative stress, VECs were treated with H2O2, and the expression of LDHA and VEGFA was analyzed using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB) assays. Under oxygen-glucose deprivation/reperfusion (OGD/R) conditions, the effects of LDHA overexpression and VEGFA knockdown on cell viability and apoptosis were evaluated. Immunoprecipitation combined with western blotting was used to detect the lactylation status of LDHA following OGD/R stimulation and treatment with lactic acid (LA) and 2-deoxyglucose (2-DG). Our results indicated that oxidative stress modulates LDHA expression, glucose uptake, and lactate production, suggesting a metabolic shift towards glycolysis. LDHA overexpression improved cell survival and reduced apoptosis, while VEGFA knockdown had the opposite effect. Additionally, 2-DG treatment reduced LDHA lactylation and apoptosis. Our findings demonstrated that LDHA plays a critical role in the oxidative stress response of VECs, highlighting the potential therapeutic value of targeting glycolysis in CA. This study contributes to the understanding of metabolic adaptations in vascular pathologies and suggests new avenues for therapeutic intervention in CA management.
PubMed: 38829380
DOI: 10.17305/bb.2024.10510 -
Frontiers in Oncology 2024Since the first report, primary mediastinal seminoma has a low incidence in the population, and it mainly affects young and middle-aged men, is clinically rare, and...
INTRODUCTION
Since the first report, primary mediastinal seminoma has a low incidence in the population, and it mainly affects young and middle-aged men, is clinically rare, and accounts for a very small proportion of mediastinal tumors. In this study, we describe the first case of primary mediastinal seminoma with azoospermia and hypothesize that the coexistence of the two disorders may not be a coincidence.
CASE REPORT
A 16-year-old man presented with chest tightness and chest pain, a mediastinal mass on chest CT, and abnormal 18F-fluoro-deoxyglucose uptake on a PET-CT scan. By biopsy of the mass, the pathological diagnosis was a primary mediastinal seminoma. Because chemotherapy is included in the treatment of the tumor, the patient underwent sperm freezing before treatment, considering that chemotherapy can affect fertility, but the patient was diagnosed with azoospermia. Finally, the patient underwent tumor resection and postoperative chemotherapy. No tumor recurrence was observed at the current follow-up.
CONCLUSION
Primary mediastinal seminoma is mainly confirmed by histopathological examination, and surgery and chemoradiotherapy are the current treatments. In patients with mediastinal seminoma or azoospermia, doctors should be aware that the two disorders may coexist, especially in men who have fertility requirements or long-term infertility, and that examination of the mediastinum and semen may lead to unexpected findings in the diagnosis and treatment. For mediastinal germ cell tumors, genetic testing is of great value in the treatment of tumors and the prediction of associated diseases. Future studies exploring the potential correlation between mediastinal seminoma and azoospermia will be prospective.
PubMed: 38826789
DOI: 10.3389/fonc.2024.1309803 -
Journal of Musculoskeletal & Neuronal... Jun 2024Increasingly Charcot neuroarthropathy (CN) is being recognized in patients with Charcot-Marie-Tooth (CMT) disease. In this report, we describe a case of CN in a CMT...
Increasingly Charcot neuroarthropathy (CN) is being recognized in patients with Charcot-Marie-Tooth (CMT) disease. In this report, we describe a case of CN in a CMT patient, adding to the very scarce literature describing this association. We additionally report his unique evaluation with fluorodeoxyglucose (FDG) and sodium fluoride (NaF) positron emission tomography/computed tomography (PET/CT) scanning, the study of which is limited in CN despite its promising role. A 54-year-old known case of CMT, presented with left foot pain, and swelling for 4 months. Weakness and sensory deficits as a result of CMT were evident in both lower and upper limbs. His x-ray was suggestive of CN. Both FDG and NaF PET/CT scanning demonstrated increased tracer uptake in the first tarsometatarsal joint (TMTJ), in keeping with CN. Recognition of the association of CMT with CN is of vital importance as early diagnosis relies on high clinical suspicion. Characterizing risk factors of CN in CMT patients is still under study. Moreover, there is lack of data evaluating the role of PET/CT in CN and specifically in the context of CMT.
Topics: Humans; Charcot-Marie-Tooth Disease; Middle Aged; Positron Emission Tomography Computed Tomography; Male; Fluorodeoxyglucose F18; Sodium Fluoride; Arthropathy, Neurogenic; Radiopharmaceuticals
PubMed: 38826006
DOI: No ID Found -
Scientific Reports Jun 2024The aim of the study was to assess healthy tissue metabolism (HTM) using 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG) positron emission tomography/computed tomography (PET/CT)...
The aim of the study was to assess healthy tissue metabolism (HTM) using 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG) positron emission tomography/computed tomography (PET/CT) during chemotherapy in Hodgkin lymphoma (HL) and the association of HTM with baseline metabolic tumour volume (MTV), haematological parameters, adverse events (AEs), early response and progression-free survival (PFS). We retrospectively identified 200 patients with advanced HL from the RATHL trial with [F]FDG-PET/CT before (PET0) and following 2 cycles of chemotherapy (PET2). [F]FDG-uptake was measured in bone marrow (BM), spleen, liver and mediastinal blood pool (MBP). Deauville score (DS) 1-3 was used to classify responders and DS 4-5, non-responders. [F]FDG-uptake decreased significantly in BM and spleen and increased in liver and MBP at PET2 (all p < 0.0001), but was not associated with MTV. Higher BM uptake at PET0 was associated with lower baseline haemoglobin and higher absolute neutrophil counts, platelets, and white blood cells. High BM, spleen, and liver uptake at PET0 was associated with neutropenia after cycles 1-2. BM uptake at PET0 was associated with treatment failure at PET2 and non-responders with higher BM uptake at PET2 had significantly inferior PFS (p = 0.023; hazard ratio = 2.31). Based on these results, we concluded that the change in HTM during chemotherapy was most likely a direct impact of chemotherapy rather than a change in MTV. BM uptake has prognostic value in HL.
Topics: Humans; Hodgkin Disease; Fluorodeoxyglucose F18; Positron Emission Tomography Computed Tomography; Male; Female; Adult; Middle Aged; Prognosis; Retrospective Studies; Young Adult; Bone Marrow; Aged; Liver; Adolescent; Radiopharmaceuticals; Spleen
PubMed: 38824206
DOI: 10.1038/s41598-024-63349-5 -
Nature Communications May 2024Minimally invasive thermal therapy is a successful alternative treatment to surgery in solid tumors with high complete ablation rates, however, tumor recurrence remains...
Minimally invasive thermal therapy is a successful alternative treatment to surgery in solid tumors with high complete ablation rates, however, tumor recurrence remains a concern. Central memory CD8 T cells (T) play important roles in protection from chronic infection and cancer. Here we find, by single-cell RNA analysis of human breast cancer samples, that although the memory phenotype of peripheral CD8 T cells increases slightly after microwave ablation (MWA), the metabolism of peripheral CD8 T cells remains unfavorable for memory phenotype. In mouse models, glycolysis inhibition by 2-deoxy-D-glucose (2DG) in combination with MWA results in long-term anti-tumor effect via enhancing differentiation of tumor-specific CD44CD62LCD8 T cells. Enhancement of CD8 T cell differentiation determined by Stat-1, is dependent on the tumor-draining lymph nodes (TDLN) but takes place in peripheral blood, with metabolic remodeling of CD8 T cells lasting the entire course of the the combination therapy. Importantly, in-vitro glycolysis inhibition in peripheral CD8 T cells of patients with breast or liver tumors having been treated with MWA thrice leads to their differentiation into CD8 T cells. Our work thus offers a potential strategy to avoid tumor recurrence following MWA therapy and lays down the proof-of-principle for future clinical trials.
Topics: Glycolysis; Animals; CD8-Positive T-Lymphocytes; Humans; Cell Differentiation; Mice; Female; Breast Neoplasms; Microwaves; Immunologic Memory; Deoxyglucose; Cell Line, Tumor; Liver Neoplasms; Memory T Cells
PubMed: 38821965
DOI: 10.1038/s41467-024-49059-6